The present invention relates to a pharmaceutical composition comprising as active substances (a) gabapentin or pregabalin or pharmaceutically acceptable salts thereof and (b) N-type calcium channel antagonist or pharmaceutically acceptable salts thereof, those pharmaceutical composition is primarily effective for prevention, reduction and treatment of pain.
The present invention also relates to a method for preventing, reducing and treating pain using the above-mentioned active substances, and the use of these active substances.
Gabapentin is known to have a pain relief effect, although its mechanism of action remains elusive. Gabapentin is a derivative of γ-amino butyric acid (GABA), but it is shown not to bind to GABA receptors. Nonetheless, gabapentin can work to increase the concentration of GABA in human brain and the ratio of GABA synthesis. The GABA is an inhibitory neurotransmitter and GABA agonist has been identified as providing outstanding antiallodynia action in animal models, which suggests that gabapentin can exert its analgesic effects through the above-mentioned mode of action associated with GABA (Acta Neurol. Scand. 101:359-371, 2000). In addition, it is suggested that gabapentin can inhibit calcium current because gabapentin is shown to bind to the α2δ subunit of calcium channels. However, it is reported on one hand that gabapentin does not act on voltage-dependent calcium channels including N-type calcium channel (Epilepsy Res. 16:89-98, 1993); and it is reported on the other hand that gabapentin does not act on N-type calcium channel, but acts on P/Q type calcium channel (Br. J. Pharmacol. 130:900-906, 2000). Further, there is also a report concluding that gabapentin acts on all of N-, L- and P/Q type calcium channels (Br. J. Pharmacol. 135:257-265, 2002). As mentioned above, there are still a variety of different suggestions and a reliable theory has not yet been established.
Pregabalin is also a derivative of GABA and is known to share the pain control effectiveness. Although the mechanism of action associated with pregabalin has not yet been clarified, pregabalin is thought to increase the GABA concentration in nervous tissues in a similar manner of gabapentin. In addition, it is known that pregabalin works to liberate gabapentin from its binding site (Epilepsy Res. 34:1-41, 1999).
As is known, the N-type calcium channel antagonist has a pain control effect, too. The N-type calcium channel antagonist acts on the N-type calcium channels specifically positioned in the nerve system to inhibit calcium influx into the nerves. The N-type calcium channels, which are present at high density in presynaptic terminals of the afferent nociceptive nerve serving to transmit pain signals are concerned in transmission of the pain signals to central nervous system (Exp. Opin. Ther. Patents 8:1237-1250, 1998). The N-type calcium channel antagonist can inhibit the influx of calcium into the nerves via the N-type calcium channels to modulate release of the neurotransmitter and inhibit transmission of pain signals to central nervous system. In this way the N-type calcium channel antagonist can exhibit its analgesic action.
There are conventionally known some embodiments where gabapentin or pregabalin is used in combination with different kinds of pharmaceutical drugs, as cited in the following references and patent specifications:
(1) Combination of (a) gabapentin with (b) lamotrigine or carbamazepine (Eur. Neurol., vol. 44, 45-48, 2000)
(2) Combination of (a) gabapentin with (b) a non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (Anesthesiology, vol. 92, 500-506, 2000)
(3) Combination of (a) gabapentin with (b) a nonsteroidal anti-inflammatory drug, ibuprofen (Anesthesiology, vol. 91, 1006-1013, 1999)
(4) Combination of (a) gabapentin with (b) morphine (Pain, vol. 72, 375-382, 1997)
(5) Combination of (a) gabapentin or pregabalin with (b) any of an analgesic, N-methyl-D-aspartate receptor antagonist or nonsteroidal anti-inflammatory drug (WO 99/12537)
(6) Combination of (a) gabapentin or pregabalin with (b) a sodium channel inhibitor (WO 00/61188)
Nonetheless, there is not known any pharmaceutical composition comprising as active substances (a) gabapentin or pregabalin or pharmaceutically acceptable salts thereof and (b) N-type calcium channel antagonist or pharmaceutically acceptable salts thereof, and there is not recognized any effect as obtained by the use of gabapentin or pregabalin together with N-type calcium channel antagonist.
Further, WO2001/76576 discloses a pharmaceutical composition for treatment of pain and migraine, comprising (a) nicotine receptor partial agonist, (b) analgesic, and (c) pharmaceutically acceptable carrier. According to the disclosure, the component (b) of the above-mentioned pharmaceutical composition, that is, an analgesic drug, includes anticonvulsants, N-type calcium channel inhibitors or the like, wherein as the anticonvulsant gabapentin, pregabalin or the like is used. However, WO2001/76576 discloses a pharmaceutical composition for treatment of pain and migraine, characterized by comprising the three components (a), (b) and (c), and the composition can achieve its efficacy resulting from the combined use of the three components (a), (b) and (c). There is no description about a pharmaceutical composition of the present invention which comprises as active substances (a) gabapentin or pregabalin or pharmaceutically acceptable salts thereof and (b) N-type calcium channel antagonist or pharmaceutically acceptable salts thereof. No description is found that suggests the effects as obtained by the combined use of (a) gabapentin or pregabalin or pharmaceutically acceptable salts thereof with (b) N-type calcium channel antagonist or pharmaceutically acceptable salts thereof.
In the area of prevention and treatment of pain, there is an increasing demand for a significantly improved pharmaceutical drug with potentiated efficacy as compared with the conventional ones, with producing no side effects. For example, evaluation by the patients with post-herpetic neuralgia reported that the treatment effectiveness for gabapentin reached approximately 60% (Acta Neurol. Scand. 101:359-371, 2000). To further potentiate the efficacy is therefore considered to be of great significance in the treatment of pain.
Gabapentin at high doses is needed when gabapentin is used for the treatment of pain. However, it has been proved that gabapentin at high doses produce side effects such as somnolence, dizziness and ataxia (Pharmacol. Ther. 88:163-185, 2000)
Also, a significant depression of motor system has been observed in rats at high doses of pregabalin (Br. J. Pharmacol. 121: 1513-1522, 1997), and in addition, development of side effects associated with pregabalin including somnolence and dizziness has been recognized in clinical tests (Neurology. 54(S3): A421, 2000).
Accordingly, there is an increasing demand for a pain control therapy capable of lowering an incidence of side effects which are recognized in many of the currently available treatments of pain.